@article{LamatschTrifonovSchoriesetal.2011, author = {Lamatsch, D. K. and Trifonov, V. and Schories, S. and Epplen, J. T. and Schmid, M. and Schartl, M.}, title = {Isolation of a Cancer-Associated Microchromosome in the Sperm-Dependent Parthenogen Poecilia formosa}, series = {Cytogenetic and Genome Research}, volume = {135}, journal = {Cytogenetic and Genome Research}, number = {2}, issn = {1424-8581}, doi = {10.1159/000331271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196785}, pages = {135-142}, year = {2011}, abstract = {In the asexual all-female fish species Poecilia formosa, the Amazon molly, supernumerary chromosomes have frequently been found in both laboratory-reared and wild-caught individuals. While wild-caught individuals with B chromosomes are phenotypically indifferent from conspecifics, individuals carrying B chromosomes from recent introgression events in the laboratory show phenotypic changes. Former analyses showed that the expression of a pigment cell locus is associated with the presence of these B chromosomes. In addition, they contain a so far unidentified locus that confers a higher susceptibility to tumor formation in the presence of pigmentation pattern. Isolation by microdissection and hybridization to metaphase chromosomes revealed that they contain one or several sequences with similarity to a highly repetitive pericentromeric and subtelomeric sequence in A chromosomes. Isolation of one particular sequence by AFLP showed that the B chromosomes contain at least 1 copy of an A-chromosomal region which is highly conserved in the whole genus Poecilia, i.e. more than 5 million years old. We propose it to be a single copy sequence.}, language = {en} } @article{SchneiderElHajjHaaf2014, author = {Schneider, Eberhard and El Hajj, Nady and Haaf, Thomas}, title = {Epigenetic Information from Ancient DNA Provides New Insights into Human Evolution}, series = {Brain, Behavior and Evolution}, volume = {84}, journal = {Brain, Behavior and Evolution}, number = {3}, issn = {0006-8977}, doi = {10.1159/000365650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196800}, pages = {169-171}, year = {2014}, abstract = {No abstract available.}, language = {en} } @article{CamachoSchmidCabrero2011, author = {Camacho, J.P.M. and Schmid, M. and Cabrero, J.}, title = {B Chromosomes and Sex in Animals}, series = {Sexual Development}, volume = {5}, journal = {Sexual Development}, number = {3}, issn = {1661-5425}, doi = {10.1159/000324930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196321}, pages = {155-166}, year = {2011}, abstract = {Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome.}, language = {en} } @article{PootHaaf2015, author = {Poot, Martin and Haaf, Thomas}, title = {Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements}, series = {Molecular Syndromology}, volume = {6}, journal = {Molecular Syndromology}, number = {3}, issn = {1661-8769}, doi = {10.1159/000438812}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196524}, pages = {110-134}, year = {2015}, abstract = {Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.}, language = {en} } @article{HeinrichNandaRehnetal.2013, author = {Heinrich, T. and Nanda, I. and Rehn, M. and Zollner, U. and Frieauff, E. and Wirbelauer, J. and Grimm, T. and Schmid, M.}, title = {Live-Born Trisomy 22: Patient Report and Review}, series = {Molecular Syndromology}, volume = {3}, journal = {Molecular Syndromology}, number = {6}, issn = {1661-8769}, doi = {10.1159/000346189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196535}, pages = {262-269}, year = {2013}, abstract = {Trisomy 22 is a common trisomy in spontaneous abortions. In contrast, live-born trisomy 22 is rarely seen due to severe organ malformations associated with this condition. Here, we report on a male infant with complete, non-mosaic trisomy 22 born at 35 + 5 weeks via caesarean section. Peripheral blood lymphocytes and fibroblasts showed an additional chromosome 22 in all metaphases analyzed (47,XY,+22). In addition, array CGH confirmed complete trisomy 22. The patient's clinical features included dolichocephalus, hypertelorism, flattened nasal bridge, dysplastic ears with preauricular sinuses and tags, medial cleft palate, anal atresia, and coronary hypospadias with scrotum bipartitum. Essential treatment was implemented in close coordination with the parents. The child died 29 days after birth due to respiratory insufficiency and deterioration of renal function. Our patient's history complements other reports illustrating that children with complete trisomy 22 may survive until birth and beyond.}, language = {en} } @article{AlmanzarKleinSchmalzingetal.2016, author = {Almanzar, Giovanni and Klein, Matthias and Schmalzing, Marc and Hilligardt, Deborah and El Hajj, Nady and Kneitz, Hermann and Wild, Vanessa and Rosenwald, Andreas and Benoit, Sandrine and Hamm, Henning and Tony, Hans-Peter and Haaf, Thomas and Goebeler, Matthias and Prelog, Martina}, title = {Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis}, series = {International Archives of Allergy and Immunology}, volume = {171}, journal = {International Archives of Allergy and Immunology}, number = {2}, issn = {1018-2438}, doi = {10.1159/000450949}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196577}, pages = {141-154}, year = {2016}, abstract = {Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.}, language = {en} } @article{SchmidSteinlein2016, author = {Schmid, Michael and Steinlein, Claus}, title = {Chromosome Banding in Amphibia. XXXIV. Intrachromosomal Telomeric DNA Sequences in Anura}, series = {Cytogenetic and Genome Research}, volume = {148}, journal = {Cytogenetic and Genome Research}, number = {2-3}, issn = {1424-8581}, doi = {10.1159/000446298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196693}, pages = {211-226}, year = {2016}, abstract = {The mitotic chromosomes of 4 anuran species were examined by various classical banding techniques and by fluorescence in situ hybridization using a (TTAGGG)\(_n\) repeat. Large intrachromosomal telomeric sequences (ITSs) were demonstrated in differing numbers and chromosome locations. A detailed comparison of the present results with numerous published and unpublished data allowed a consistent classification of the various categories of large ITSs present in the genomes of anurans and other vertebrates. The classification takes into consideration the total numbers of large ITSs in the karyotypes, their chromosomal locations and their specific distribution patterns. A new category of large ITSs was recognized to exist in anuran species. It consists of large clusters of ITSs located in euchromatic chromosome segments, which is in clear contrast to the large ITSs in heterochromatic chromosome regions known in vertebrates. The origin of the different categories of large ITSs in heterochromatic and euchromatic chromosome regions, their mode of distribution in the karyotypes and evolutionary fixation in the genomes, as well as their cytological detection are discussed.}, language = {en} } @article{SchmidSteinleinLombetal.2016, author = {Schmid, Michael and Steinlein, Claus and Lomb, Christian and Sperling, Karl and Neitzel, Heidemarie}, title = {5-Methylcytosine-Rich Heterochromatin in the Indian Muntjac}, series = {Cytogenetic and Genome Research}, volume = {147}, journal = {Cytogenetic and Genome Research}, number = {4}, issn = {1424-8581}, doi = {10.1159/000444431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196701}, pages = {240-246}, year = {2016}, abstract = {Two 5-methylcytosine (5-MeC)-rich heterochromatic regions were demonstrated in metaphase chromosomes of the Indian muntjac by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. The metaphases were obtained from diploid and triploid cell lines. A major region is located in the 'neck' of the 3;X fusion chromosome and can be detected after denaturation of the chromosomal DNA with UV-light irradiation for 1 h. It is located exactly at the border of the X chromosome and the translocated autosome 3. A minor region is found in the centromeric region of the free autosome 3 after denaturing the chromosomal DNA for 3 h or longer. The structure and possible function of the major hypermethylated region as barrier against spreading of the X-inactivation process into the autosome 3 is discussed.}, language = {en} } @article{SchmidSteinleinYanoetal.2016, author = {Schmid, Michael and Steinlein, Claus and Yano, Cassia F. and Cioffi, Marcelo B.}, title = {Hypermethylated Chromosome Regions in Nine Fish Species with Heteromorphic Sex Chromosomes}, series = {Cytogenetic and Genome Research}, volume = {147}, journal = {Cytogenetic and Genome Research}, number = {2-3}, issn = {1424-8581}, doi = {10.1159/000444067}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196710}, pages = {169-178}, year = {2016}, abstract = {Sites and amounts of 5-methylcytosine (5-MeC)-rich chromosome regions were detected in the karyotypes of 9 Brazilian species of Characiformes fishes by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. These species, belonging to the genera Leporinus, Triportheus and Hoplias, are characterized by highly differentiated and heteromorphic ZW and XY sex chromosomes. In all species, the hypermethylated regions are confined to constitutive heterochromatin. The number and chromosome locations of hypermethylated heterochromatic regions in the karyotypes are constant and species-specific. Generally, heterochromatic regions that are darkly stained by the C-banding technique are distinctly hypermethylated, but several of the brightly fluorescing hypermethylated regions merely exhibit moderate or faint C-banding. The ZW and XY sex chromosomes of all 9 analyzed species also show species-specific heterochromatin hypermethylation patterns. The analysis of 5-MeC-rich chromosome regions contributes valuable data for comparative cytogenetics of closely related species and highlights the dynamic process of differentiation operating in the repetitive DNA fraction of sex chromosomes.}, language = {en} } @article{SchmidSteinlein2015, author = {Schmid, Michael and Steinlein, Claus}, title = {Chromosome Banding in Amphibia. XXXII. The Genus Xenopus (Anura, Pipidae)}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000433481}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196727}, pages = {201-217}, year = {2015}, abstract = {Mitotic chromosomes of 16 species of the frog genus Xenopus were prepared from kidney and lung cell cultures. In the chromosomes of 7 species, high-resolution replication banding patterns could be induced by treating the cultures with 5-bromodeoxyuridine (BrdU) and deoxythymidine (dT) in succession, and in 6 of these species the BrdU/dT-banded chromosomes could be arranged into karyotypes. In the 3 species of the clade with 2n = 20 and 4n = 40 chromosomes (X. tropicalis, X. epitropicalis, X. new tetraploid 1), as well as in the 3 species with 4n = 36 chromosomes (X. laevis, X. borealis, X. muelleri), the BrdU/dT-banded karyotypes show a high degree of homoeology, though differences were detected between these groups. Translocations, inversions, insertions or sex-specific replication bands were not observed. Minor replication asynchronies found between chromosomes probably involve heterochromatic regions. BrdU/dT replication banding of Xenopus chromosomes provides the landmarks necessary for the exact physical mapping of genes and repetitive sequences. FISH with an X. laevis 5S rDNA probe detected multiple hybridization sites at or near the long-arm telomeric regions in most chromosomes of X. laevis and X. borealis, whereas in X. muelleri, the 5S rDNA sequences are located exclusively at the long-arm telomeres of a single chromosome pair. Staining with the AT base pair-specific fluorochrome quinacrine mustard revealed brightly fluorescing heterochromatic regions in the majority of X. borealis chromosomes which are absent in other Xenopus species.}, language = {en} } @article{SchmidEvansBogart2015, author = {Schmid, Michael and Evans, Ben J. and Bogart, James P.}, title = {Polyploidy in Amphibia}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000431388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196730}, pages = {315-330}, year = {2015}, abstract = {This review summarizes the current status of the known extant genuine polyploid anuran and urodelan species, as well as spontaneously originated and/or experimentally produced amphibian polyploids. The mechanisms by which polyploids can originate, the meiotic pairing configurations, the diploidization processes operating in polyploid genomes, the phenomenon of hybridogenesis, and the relationship between polyploidization and sex chromosome evolution are discussed. The polyploid systems in some important amphibian taxa are described in more detail.}, language = {en} } @article{MatsudaUnoKondoetal.2015, author = {Matsuda, Yoichi and Uno, Yoshinobu and Kondo, Mariko and Gilchrist, Michael J. and Zorn, Aaron M. and Rokhsar, Daniel S. and Schmid, Michael and Taira, Masanori}, title = {A New Nomenclature of Xenopus laevis Chromosomes Based on the Phylogenetic Relationship to Silurana/Xenopus tropicalis}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000381292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196748}, pages = {187-191}, year = {2015}, abstract = {Xenopus laevis (XLA) is an allotetraploid species which appears to have undergone whole-genome duplication after the interspecific hybridization of 2 diploid species closely related to Silurana/Xenopus tropicalis (XTR). Previous cDNA fluorescence in situ hybridization (FISH) experiments have identified 9 sets of homoeologous chromosomes in X. laevis, in which 8 sets correspond to chromosomes 1-8 of X. tropicalis (XTR1-XTR8), and the last set corresponds to a fusion of XTR9 and XTR10. In addition, recent X. laevis genome sequencing and BAC-FISH experiments support this physiological relationship and show no gross chromosome translocation in the X. laevis karyotype. Therefore, for the benefit of both comparative cytogenetics and genome research, we here propose a new chromosome nomenclature for X. laevis based on the phylogenetic relationship and chromosome length, i.e. XLA1L, XLA1S, XLA2L, XLA2S, and so on, in which the numbering of XLA chromosomes corresponds to that in X. tropicalis and the postfixes 'L' and 'S' stand for 'long' and 'short' chromosomes in the homoeologous pairs, which can be distinguished cytologically by their relative size. The last chromosome set is named XLA9L and XLA9S, in which XLA9 corresponds to both XTR9 and XTR10, and hence, to emphasize the phylogenetic relationship to X. tropicalis, XLA9_10L and XLA9_10S are also used as synonyms.}, language = {en} } @article{SchmidSteinleinFeichtingeretal.2014, author = {Schmid, Michael and Steinlein, Claus and Feichtinger, Wolfgang and Haaf, Thomas and Mijares-Urrutia, Abraham and Schargel, Walter E. and Hedges, S. Blair}, title = {Cytogenetic Studies on Gonatodes (Reptilia, Squamata, Sphaerodactylidae)}, series = {Cytogenetic and Genome Research}, volume = {144}, journal = {Cytogenetic and Genome Research}, number = {1}, issn = {1424-8581}, doi = {10.1159/000367929}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196753}, pages = {47-61}, year = {2014}, abstract = {Mitotic and meiotic chromosomes of 5 species of the reptile genus Gonatodes are described by means of conventional staining, banding analyses and in situ hybridization using a synthetic telomeric DNA probe. The amount, location and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes of G. falconensis and G. taniae from northern Venezuela are distinguished by their extraordinarily reduced diploid chromosome number of 2n = 16, which is the lowest value found so far in reptiles. In contrast to most other reptiles, both species have exclusively large biarmed (meta- and submetacentric) chromosomes. Comparison of the karyotypes of G. falconensis and G. taniae with those of other Gonatodes species indicates that the exceptional 2n = 16 karyotype originated by a series of 8 centric fusions. The karyotypes of G. falconensis and G. taniae are further characterized by the presence of considerable amounts of (TTAGGG)n telomeric sequences in the centromeric regions of all chromosomes. These are probably not only relics of the centric fusion events, but a component of the highly repetitive DNA in the constitutive heterochromatin of the chromosomes. The genome sizes of 4 Gonatodes species were determined using flow cytometry. For comparative purposes, all previously published cytogenetic data on Gonatodes and other sphaerodactylids are included and discussed.}, language = {en} } @article{SchmidSteinleinFeichtingeretal.2014, author = {Schmid, Michael and Steinlein, Claus and Feichtinger, Wolfgang and Bogart, James P.}, title = {Chromosome Banding in Amphibia. XXXI. The Neotropical Anuran Families Centrolenidae and Allophrynidae}, series = {Cytogenetic and Genome Research}, volume = {142}, journal = {Cytogenetic and Genome Research}, number = {4}, issn = {1424-8581}, doi = {10.1159/000362216}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196763}, pages = {268-285}, year = {2014}, abstract = {The mitotic chromosomes of 11 species from the anuran families Centrolenidae and Allophrynidae were analyzed by means of conventional staining, banding techniques, and in situ hybridization. The amount, location, and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes were found to be highly conserved with a low diploid chromosome number of 2n = 20 and morphologically similar chromosomes. The sister group relationship between the Centrolenidae and Allophrynidae (unranked taxon Allocentroleniae) is clearly corroborated by the cytogenetic data. The existence of heteromorphic XY♂/XX♀ sex chromosomes in an initial stage of morphological differentiation was confirmed in Vitreorana antisthenesi. The genome sizes of 4 centrolenid species were determined using flow cytometry. For completeness and for comparative purposes, all previously published cytogenetic data on centrolenids are included.}, language = {en} } @article{FockenSteinemannSkawranetal.2011, author = {Focken, T. and Steinemann, D. and Skawran, B. and Hofmann, W. and Ahrens, P. and Arnold, N. and Kroll, P. and Kreipe, H. and Schlegelberger, B. and Gadzicki, D.}, title = {Human BRCA1-associated breast cancer: No increase in numerical chromosomal instability compared to sporadic tumors}, series = {Cytogenetic and Genome Research}, volume = {135}, journal = {Cytogenetic and Genome Research}, number = {2}, issn = {1424-8581}, doi = {10.1159/000332005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196770}, pages = {84 -- 92}, year = {2011}, abstract = {BRCA1 is a major gatekeeper of genomic stability. Acting in multiple central processes like double-strand break repair, centrosome replication, and checkpoint control, BRCA1 participates in maintaining genomic integrity and protects the cell against genomic instability. Chromosomal instability (CIN) as part of genomic instability is an inherent characteristic of most solid tumors and is also involved in breast cancer development. In this study, we determined the extent of CIN in 32 breast cancer tumors of women with a BRCA1 germline mutation compared to 62 unselected breast cancers. We applied fluorescence in situ hybridization (FISH) with centromere-specific probes for the chromosomes 1, 7, 8, 10, 17, and X and locus-specific probes for 3q27 (BCL6), 5p15.2 (D5S23), 5q31 (EGR1), 10q23.3 (PTEN), and 14q32 (IGH@) on formalin-fixed paraffin-embedded tissue microarray sections. Our hypothesis of an increased level of CIN in BRCA1-associated breast cancer could not be confirmed by this approach. Surprisingly, we detected no significant difference in the extent of CIN in BRCA1-mutated versus sporadic tumors. The only exception was the CIN value for chromosome 1. Here, the extent of CIN was slightly higher in the group of sporadic tumors.}, language = {en} } @article{MaierhoferFlunkertOshimaetal.2019, author = {Maierhofer, Anna and Flunkert, Julia and Oshima, Junko and Martin, George M. and Poot, Martin and Nanda, Indrajit and Dittrich, Marcus and M{\"u}ller, Tobias and Haaf, Thomas}, title = {Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes}, series = {Aging Cell}, volume = {18}, journal = {Aging Cell}, doi = {10.1111/acel.12995}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202733}, pages = {e12995}, year = {2019}, abstract = {Werner Syndrome (WS) is an adult-onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN-mutant) or atypical WS (3 LMNA-mutant and 3 POLD1-mutant) patients and age- and sex-matched controls. WS was not associated with either age-related accelerated global losses of ALU, LINE1, and α-satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN-mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence-specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS- and age-related methylation changes exhibited a constant offset of methylation between WRN-mutant patients and controls across the entire analyzed age range. WS-specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.}, language = {en} } @article{ElHajjDittrichBoecketal.2016, author = {El Hajj, Nady and Dittrich, Marcus and B{\"o}ck, Julia and Kraus, Theo F. J. and Nanda, Indrajit and M{\"u}ller, Tobias and Seidmann, Larissa and Tralau, Tim and Galetzka, Danuta and Schneider, Eberhard and Haaf, Thomas}, title = {Epigenetic dysregulation in the developing Down syndrome cortex}, series = {Epigenetics}, volume = {11}, journal = {Epigenetics}, number = {8}, doi = {10.1080/15592294.2016.1192736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191239}, pages = {563-578}, year = {2016}, abstract = {Using Illumina 450K arrays, 1.85\% of all analyzed CpG sites were significantly hypermethylated and 0.31\% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.}, language = {en} } @article{MartratMaxwellTominagaetal.2011, author = {Martrat, Griselda and Maxwell, Christopher A. and Tominaga, Emiko and Porta-de-la-Riva, Montserrat and Bonifaci, N{\´u}ria and G{\´o}mez-Bald{\´o}, Laia and Bogliolo, Massimo and L{\´a}zaro, Conxi and Blanco, Ignacio and Brunet, Joan and Neveling, Kornelia and et al,}, title = {Exploring the link between MORF4L1 and risk of breast cancer}, series = {Breast Cancer Research}, volume = {13}, journal = {Breast Cancer Research}, number = {R40}, doi = {10.1186/bcr2862}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169119}, pages = {1-14}, year = {2011}, abstract = {Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.}, language = {en} } @article{RodriguezMariWilsonTitusetal.2011, author = {Rodr{\´i}guez-Mari, Adriana and Wilson, Catherine and Titus, Tom A. and Canestro, Cristian and BreMiller, Ruth A. and Yan, Yi-Lin and Nanda, Indrajit and Johnston, Adam and Kanki, John P. and Gray, Erin M. and He, Xinjun and Spitsbergen, Jan and Schindler, Detlev and Postlethwait, John H.}, title = {Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {3}, doi = {10.1371/journal.pone.0026377}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142285}, pages = {e1001357}, year = {2011}, abstract = {Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: (25.0 +/- 2.8) years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes (V(gray)) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of (23.6 +/- 0.7) mm considering the deepest 5\% of light. Of the detected photon packages scalp and bone absorbed (96.4 +/- 9: 7)\% and V(gray) absorbed (3.1 +/- 1.8)\% of the energy. The mean V(gray) volume (1.1 +/- 0.4)cm(3) was negatively correlated (r = - .76) with the SCD and frontal sinus volume (r = - .57) and was reduced by 41.5\% in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD (r = .46) and the traversed frontal sinus volume (r = .43). Sulcal morphology had no significant impact on V(gray). Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance.}, language = {en} } @article{WeisSchoenVictoretal.2011, author = {Weis, Eva and Schoen, Holger and Victor, Anja and Spix, Claudia and Ludwig, Marco and Schneider-Raetzke, Brigitte and Kohlschmidt, Nicolai and Bartsch, Oliver and Gerhold-Ay, Aslihan and Boehm, Nils and Grus, Franz and Haaf, Thomas and Galetzka, Danuta}, title = {Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0025750}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141838}, pages = {e25750}, year = {2011}, abstract = {Background: The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. Methodology/Findings: To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy gamma-irradiated cells of two-cancer patients. Conclusions/Significance: Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.}, language = {en} }